Sustained Release from Precirol® (Glycerol Palmito-Stearate) Matrix. Effect of Mannitol and Hydroxypropyl Methylcellulose on the Release of Theophylline

Abstract

The release of theophylline embedded in a Precirol® (glycerol palmitostearate) matrix containing varying amounts of mannitol and/or hydroxypropyl methyl cellulose 4000 (HPMC) was studied. The results indicated that HPMC or mannitol when incorporated alone, the drug release followed the diffusion-controlled matrix model where the quantity of drug released was proportional to the square root of time. The release rate was found to increase with increase in the amount of HPMC or mannitol in the matrix. When both mannitol and HPMC were incorporated in the matrix, the mechanism of release changed from the Higuchi model to a first-order release. A linear relationship was found between the fraction of HPMC or mannitol in the matrix and the rate constant. An optimum combination of Precirol®, mannitol and HPMC was found for a 12 hour theophyll ine sustained release preparation     

The Use of Precirol® to Prepare Sustained Release Tablets of Theophylline and Quinidine Gluconate

Abstract

Tablets were made using theophylline, lactose and Precirol by a granulation technique, resulting in more than 12 hours release. Granulation and hot fusion methods were used to prepare admixtures of quinidine gluconate and Precirol at different ratios of Precirol: drug, 1:9, 3:7 and 1:1. Dissolution studies in 0.1N HCl showed drastic differences in the release of quinidine gluconate from tablets made by the two different methods; granulation method gave a faster release while the hot fusion method gave slower and incomplete release at higher Precirol content. The release rate decreases with higher Precirol content.     

Inclusion Complexes of Tolnaftate with β-Cyclodextrin and Hydroxypropyl β-Cyclodextrin

Abstract

Tolnaftate, an antifungal agent, was found to form inclusion complexes with both β-cyclodextrin (β-CD) and hydroxypropyl β-cyclodextrins (HPBCDs) with two different degrees of substitution [HPBCD(A)-8% and HPBCD(B)-3%]. Complex formation in the solution state was studied using phase solubility and spectral shift methods. Solid complexes were prepared by the coprecipitation method. Solubilities and dissolution rates were determined for each solid complex, its corresponding physical mixture, and free drug. The increase in solubility of tolnaftate with added HPBCD was found to be significantly greater than with added β-CD. For both HPBCD(A) and HPBCD(B), over the concentration range 0–0.05 M. 1:1 complexes with stability constants of 1460 ± 139 M^-1 and 1860 ± 165 M^-1 were observed, respectively. Over the β-CD concentration range 0–0.02 M, a 1:1 complex with a stability constant of 1190 ± 105 M^-1 was observed. At higher HPBCD concentrations, the increase in solubility was observed to show a positive deviation from linearity (type A_p phase diagram). Using the spectral method, in a 2 5% v/v methanol in water system, the stability constants were determined to be 1020 ± 150 M^-1 1110 ± 120 M^-1 and 1100 ± 260 M^-1 for HPBCD(A), HPBCD(B) and β-CD, respectively. The solid complexes prepared showed improved dissolution over physical mixtures and free drug.     

Mechanistic Analysis of Drug Release from Theophylline Pellets Coated by Films Containing Pectin,Chitosan and Eudragit® RS

The objective of this study was to obtain detailed information on the mechanism of drug release from mixed-film of pectin-chitosan/Eudragit® RS. Pellets (710–840 μm in diameter) containing 60% theophylline and 40% microcrystalline cellulose were prepared by extrusion-spheronization method. Eudragit® L100-55 enteric coating capsules included film-coated pellets of theophylline in theoretical coating weight gains of 10, 15, and 20%, with pectin-chitosan complex contents of 5, 10, 15, and 20% for each level of weight gain were prepared and subjected to in vitro drug release. Drug release from this system showed a bimodal release profile characteristic with the drug release enhancement, being triggered (burst release) in the colonic medium. The reason for burst drug release may be due to the enzymatic degradation of pectin via pectinolytic enzymes in the simulated colonic medium. The mechanism of drug release from each formulation was evaluated in the terms of zero-order, first-order, Higuchi and Korsmeyer-Peppas models. It was observed that none of the enteric coating capsules showed any drug release in the simulated gastric medium (phase I). The analysis of release profiles showed that zero-order kinetics was found as the better fitting model for all formulations in the simulated small intestine (phase II) and it could be due to the pectin-chitosan swelling and subsequent formation of aqueous channels. In the colonic medium (phase III), due to degradation of pectin and its leaching from the mixed-film, there was a modification in drug release kinetics from swelling-controlled at phase II to anomalous at phase III. It also was found that both zero-order and Higuchi models contributed in colonic drug release from most of the formulations.     

Influence of Hydroxypropyl β-Cyclodextrin on Solubility and Dissolution Profile of Ketoprofen in Its Solid Dispersions

Abstract

Solid dispersions of hydroxypropyl β-cyclodextrins (HPB), a highly water soluble derivative of β-cyclodextrin and ketoprofen (KPF), were prepared by kneading, coevaporation, and freeze-drying. X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy were used to investigate characteristics of the solid dispersions and to study the possibility of complexation of the drug with HPB. A marked difference in characteristics of dispersions was observed due to their methods of preparation. The solubility of KPF in the solid dispersions was studied by the dispersed powder technique and was found to have improved considerably over that of the drug pure alone. The dispersions had good compressibiliry. Tablets so compressed displayed good dissolution profiles.     

Photovoltaic Properties of the Modified n-Si（111） Electrodes with Ethyl and Carboxyls

n-Si（111） surface tailed -C2H5, -C2H4COOH, -C2H2COOH were prepared by the reactions among Si-H to ethyl-Grignard, methyl acrylate and ethyl propionate, and the carboxyls were formed under the existence of trifluoroacetic acid. The composite n-Si（111） electrodes were obtained by depositing Pt nanodots and the photovoltaic characteristics for these electrodes were studied in I^-/I3^- redox electrolyte. The j-U （photo current density-potential） behaviors of photo-voltage and photocurrent densities to the electrodes under solar illumination varied regularly with groups of -C2H2COOH〉-C2H4COOH〉-H〉-C2H5. The photo-voltage and photocurrent density of the electrode tailed -C2 H2COOH were -0.641 V and 5.25 mA/cm^2, respectively, more negative than those of the non-conjugated modification.     

Preparation and Characterization of Ultrafine ZrO_ Powders from Solvent Extraction of Zr(Ⅳ) with Tri-n-butyl Phosphate in Kerosene from Nitric Acid Solutions

Zr(IV) was extracted by tri-n-butyl phosphate in kerosene from concentrated nitric acid solutions and the formation of the third phase during extraction was experimentally investigated. Zirconia powders were prepared by using the loaded organic phase as the bulk solution precipitated with aqueous ammonia or NaOH solution. The powder prepared was characterized with TEM, XRD,EDAX and TG-DTA. Effects of some conditions on powder preparation were studied and it was shown that nanosized particles could be obtained from this extraction system but conditions should be carefully controlled for powder purity and particle size.     

Thermomechanical characterization of asphalt mixtures modified with high contents of asphalt shingle modifier (ASM®) and reclaimed asphalt pavement (RAP)

The reuse of reclaimed asphalt pavements (RAP) in asphalt mixes at high substitution rates has become a major economical and environmental necessity. However, this reuse of RAP is technically limited by the impact of RAP on the behavior of the mixes and industrially limited by the incorporation capacity of RAP in plants. On the other hand, several studies and industrial experiences showed that the reuse of manufacturer-waste asphalt roofing shingles as a modifier in asphalt mixes enhances the behavior of the asphalt mixes at different levels (fatigue, rutting and stiffness) without having a negative impact on low-temperature cracking when an appropriate asphalt mix design is used. The objective of this paper is to assess the behavior of asphalt mixes using a combination of RAP and asphalt shingle modifier (ASM^®) together at high substitution rates. An experimental program was set up and carried out at the Lafarge Research Center and the French Ecole Nationale des Travaux Publics de l’Etat. A reference mix, and other mixes, modified with different percentages of RAP and ASM^® were evaluated. The experimental results showed that the mixes with up to 15 % of RAP and 5 % of RAS behave well compared to the reference mix. Beyond these limits, low-temperature cracking behavior could be altered. Certain technical solutions were then evaluated and are presented in this paper.     

Experimental Determination of Densities and Isobaric Vapor–Liquid Equilibria of Methyl Acetate and Ethyl Acetate with Alcohols (C3 and C4) at 0.3 MPa

The densities and excess volumes were determined at 298.15 K for the methyl acetate + 1-propanol, methyl acetate + 1-butanol, and ethyl acetate + 1-butanol mixtures. The vapor–liquid equilibria data at 0.3 MPa for these binary systems were obtained using a stainless steel equilibrium still. The activity coefficients were obtained from the experimental data using the Hayden and O’Connell method and the Yen and Woods equation. The binary systems in this study showed positive deviations from ideality. The experimental VLE data were verified with the point-to-point test of van Ness using the Barker routine and the Fredenslund criterion. The different versions of the UNIFAC and the ASOG group contribution models were applied.     

Synthesis and Characterization of Cu Nanoparticles Embedded in PAN/β-Cyclodextrin (β-CD) Composite Nanofiber Films

In the study, PAN/β-cyclodextrin (β-CD) one dimensional composite nanofibers were synthesized with sol-gel method and electrospinning, and then, we dipped the composite nanofibers into NaBH₄ aqueous solution acted as reducing agent to fabricate PAN/β-CD/Cu composite nanofibers. We got the PAN/β-CD/Cu composite nanofibers with different concentration of β-CD, and Cu nanoparticles formed on its surface. The final products were characterized using scanning electronic microscope (SEM), fourier transform infrared spectroscopy (FTIR) and transmission electron microscope (TEM). The results of characterization showed that the Cu nanoparticles with small size were well-distributed on the composite nanofibers.     

Preparation and properties of polyrotaxane from α-cyclodextrin and poly(ethylene glycol) with poly(vinyl alcohol)

α–Cyclodextrin (α-CD) was found to form inclusion complexes with poly(ethylene glycol) (PEG) having a crystalline state in high yields, which have been investigated extensively in the past. Formation of an inclusion complex depends strongly on structure, molecular weight and geometry of the polymer. Development of a dicomponent inclusion complex (DIC) of PEG and α-CD in the presence of poly(vinyl alcohol) (PVA) and initiation of hexagonal crystals upon sonication have exhibited various microstructures. Formation of the new inclusion complex in PVA heavily depends on the concentration of PVA, temperature and sonication time. The complexes produced are characterized by FTIR, HNMR spectra and powder X-ray. ¹HNMR of the complexes demonstrate that their stoichiometric ratio is 2:1 (two ethylene glycol units and one α-CD). X-ray patterns of PEG–α-CD complex indicate that the α-CD forms channels whereas PEG/α-CD/PVA creates cage-type structures.     

Skin sensitization study of two hydroxypropyl methylcellulose components (Benecel® and E4M®) of an injectable bone substitute in guinea pigs

Although initial results were promising for an injectable bone substitute (IBS) associating a hydroxypropyl methylcellulose (HPMC) polymer vector (Benecel®, 2 w/w %) with biphasic calcium phosphate (BCP), a sensitization reaction occurred probably related to the degree of polymer purity. In this context, Benecel® and another HPMC, E4M® were investigated in the present study. The expected composition of the polymers was confirmed by gas–liquid chromatography. Studies in the guinea pig showed that Benecel® has strong sensitization capacity and E4M® none. Benecel® manifests impurities (30 times more than E4M®) in individual fibers or rounded clumps that are apparently responsible for extreme sensitization. Purification by ultracentrifugation associated with 0.2 m filtration can decrease sensitization capacity considerably, though with a slight loss of polymer concentration. Fourier transform infrared (FTIR) analysis showed that the impurities were largely cellulose derivatives. However, extraction by organic solvent, followed by FTIR studies and micro-X analysis, detected an oily substance containing carbon and silicon associated with the cellulose derivatives. E4M®, a polymer with no sensitization capacity, could replace Benecel® and improve results with IBS.     

“In-Vitro” Testing of an Antacid Formulation with Prolonged Gastric Residence Time (Almagate Flot-Coat®)

Abstract

Dynamic in vitro tests were used to study sensitivity to environmental acidity, buffering profile and residence time under simulated gastric conditions of pharmaceutical formulations incorporating the concept of prolonged gastric residence time (Almagate Flot-Coat^rG). In comparison with classical antacid products the new formulation was shown to have a high antacid potency together with a prolonged in vitro gastric residence time.     

Molecular Encapsulation of Thalidomide with Sulfobutyl Ether-7 β-Cyclodextrin for Immediate Release Property: Enhanced In Vivo Antitumor and Antiangiogenesis Efficacy in Mice

Thalidomide's reported ability to inhibit tumor angiogenesis has led to clinical trials determining its effectiveness in combating various types of cancer. Since thalidomide exhibits low oral bioavailability due to limitations in solubility, inclusion complexation using sulfobutyl ether-7 β-cyclodextrin was used to improve the delivery of thalidomide. Our main goals were to increase the solubility, bioavailability as well as chemical stability of thalidomide through complexation with anionic β-cyclodextrin, to characterize the complex in solid state using differential scanning calorimetry, X-ray powder diffractometry, and to explore thalidomide's antitumorigenic and antiangiogenesis potential when administered orally as free and in combination with cyclodextrin to experimental animals. The aqueous solubility and aqueous alkaline stability of thalidomide was markedly increased by the SBE7βCD complexation. Thalidomide administered orally in combination with SBE7βCD, led to a significant delay in tumor formation as a result of improved cellular drug absorption, distribution through solubilization in experimental animals. The improved pharmacological efficacy of the thalidomide-cyclodextrin complex compared to free thalidomide in mouse melanoma model suggest that such a delivery system may be useful for the improved therapeutics of thalidomide, in vivo.     

Evaluation of pH-Sensitivity and Drug Release Characteristics of (Polyacrylamide-Grafted-Xanthan)–Carboxymethyl Cellulose-Based pH-Sensitive Interpenetrating Network Hydrogel Beads

Novel pH-sensitive interpenetrating network hydrogel beads of polyacrylamide-grafted-xanthan (PAAm-g-XG) and sodium carboxymethyl cellulose (NaCMC) loaded with ketoprofen were prepared and evaluated for pH sensitivity and drug release characteristics. The pH-sensitive PAAm-g-XG copolymer was synthesized by free radical polymerization under the nitrogen atmosphere followed by alkaline hydrolysis. The grafting and alkaline hydrolysis reactions were confirmed by Fourier transform infrared spectroscopy. Differential scanning calorimetry and X-ray diffraction studies were carried out to know the crystalline nature of encapsulated drug. Scanning electron microscopic study revealed that the interpenetrating polymer network (IPN) beads possess porous matrix structure in alkaline pH whereas nonporous matrix structure was observed in acidic pH. The swelling of the beads and drug release was significantly increased when pH of the medium was changed from acidic to alkaline. The results of pulsatile swelling study indicated that the IPN beads changed their swelling behavior when pH of the external medium was altered. As pH of the medium was changed from 1.2 to 7.4, a considerable increase in swelling was observed for all the beads. However, swelling process was slower than the deswelling. At higher pH values, the carboxyl functional groups of hydrogels undergo ionization and the osmotic pressure inside the beads increases resulting in higher swelling. Drug release followed case II transport mechanism in acidic medium whereas anomalous/non-Fickian transport mechanism was observed in alkaline medium.     

Material and knot properties of braided polyester (Ticron®) and bioabsorbable poly-L/D-lactide (PLDLA) 96/4 sutures

The purpose of the present study was to investigate in vitro the biomechanical material and knot properties and histomorphometrical knot properties of 3-0 braided polyester suture (Ticron) and bioabsorbable poly-L/D-lactide (PLDLA) 96/4 suture. In Ticron five throws are needed to form a secure knot, and the 1 = 1 = 1 = 1 = 1 and the 2 = 1 = 1 = 1 configurations are recommended. For PLDLA several granny and square knots formed a secure knot, but the 1 = 1 and 1 = 1 = 1 knots were the best. These PLDLA knots had lower yield force and strain at yield point, but higher stiffness than the recommended Ticron knots. The ultimate force values did not differ, but PLDLA knots had significantly higher strain at ultimate point. In the histomorphometrical analysis of the recommended knots, the PLDLA knots had a significantly smaller knot surface area than the Ticron knots. According to these results, PLDLA suture proved to be suitable for flexor tendon repair.     

Core–Shell Filament with Excellent Wound Healing Property Made of Cellulose Nanofibrils and Guar Gum via Interfacial Polyelectrolyte Complexation Spinning

Natural polymer-based sutures have attractive cytocompatibility and degradability in surgical operations. Herein, anionic cellulose nanofibrils (ACNF) and cationic guar gum (CGG) are employed to produce nontoxic CGG/ACNF composite filament with a unique core–shell structure via interfacial polyelectrolyte complexation (IPC) spinning. The comprehensive characterization and application performance of the resultant CGG/ACNF filament as a surgical suture are thoroughly investigated in comparison with silk and PGLA (90% glycolide and 10% l -lactide) sutures in vitro and in vivo, respectively. Results show that the CGG/ACNF filament with the typical core–shell structure and nervation pattern surface exhibits a high orientation index (0.74) and good mechanical properties. The tensile strength and knotting strength of CGG/ACNF suture prepared by twisting CGG/ACNF filaments increase by 69.5%, and CGG/ACNF suture has a similar friction coefficient to silk and PGLA sutures. Moreover, CGG/ACNF suture with antibiosis and cytocompatibility exhibits better growth promotion of cells than silk suture, similar to PGLA suture in vitro. In addition, the stitching experiment of mice with the CGG/ACNF suture further confirms better healing properties and less inflammation in vivo than silk and PGLA sutures do. Hence, the CGG/ACNF suture with a simple preparation method and excellent application properties is promising in surgical operations.     

Comparative Pharmacokinetics of New Theophylline Preparations as Egifilin® 200 mg and 400 mg Retard Tablets After Single Dose in Healthy Volunteers

Abstract

Pharmacokinetic properties of Egifilin® retard tablets (containing 200 or 400 mg of theophylline, EGIS Pharmaceuticals Ltd., Budapest, Hungary) were investigated in 12 healthy volunteers (six women, six men). Pharmacokinetic analysis was performed according to a one-compartment open model. The retard nature of both 200 and 400 mg tablets could be demonstrated. Comparison of the pharmacokinetic curves of women and men indicated that there was no sex difference in the pharmacokinetics of two retard tablets.

Egifilin retard tablets ensured plasma levels for almost 30 hr after single drug intake with an extremely long retard plateau between 6 and 30 hr. For study purposes, an improved rapid HPLC-UV analytical method (less than 3.5 min chromatogram) has been elaborated for the determination of theophylline in human plasma. The range of the calibration is 0.6–18 μg/ml.